Role of Viral Cofactors in AIDS

Dane projektu

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CSC - Cost-sharing contracts

Cel

The main objectives of this project are the elucidation of the role played by specific viral cofactors in AIDS and the identification of cofactor-targeted therapeutic approaches that could delay or prevent the progression of the immunodeficiency which is characteristic of AIDS.

Despite the intensive research efforts made during the last decade, our understanding of the pathogenetic mechanisms of the immune defects associated with full-blown AIDS is still limited. This limitation has significantly hindered the development of effective measures for the prevention and control of this disease. Although it has been hypothesized that viral cofactors may play an essential role in the disease progression toward AIDS, no definitive proof has been hitherto provided. Several lines of clinical and experimental evidence suggest that three recently discovered human herpesviruses, namely, human herpesvirus HHV-6, HHV-7 and HHV-8, may significantly influence the natural history of AIDS and/or some AIDS-related disorders. Understanding the role played by viral cofactors in AIDS may have critical implications both for the prophylaxis and for the therapy of AIDS.

The specific objectives of the project are the following:a) To define the role played by HHV-6, a T-lymphotropic and cytopathic virus which synergizes with HIV in vitro, in the pathogenesis of the immunological defects leading to AIDS.b) To define the role played by HHV-7, a natural antagonist of HIV in vitro, in the course of HIV infection.c) To assess the prevalence and replication of a novel herpesvirus (KSHV or HHV-8) in the course of HIV infection. To develop systems for the isolation of KSHV in vitro (the virus has never been selectively isolated in cell culture) and the study of its biological, immunological and genetic characteristics.d) To establish and study animal models of infection by human herpesviruses in macaques or in heterochimeric SCID mice. To establish and study animal models of coinfection by human herpesviruses and pathogenic simian immunodeficiency virus (SIV) or HIV.f) To identify effective therapeutic agents against HHV-6, HHV-7 or KSHV in test systems in vitro. To investigate the in vivo effects of selected compounds showing high anti-herpesvirus activity in animal models.